Oxazinoindole- and thiazinoindole derivatives

ABSTRACT

Oxazionindole derivatives characterized by having an amino(lower)alkyl radical attached to the 1 position of a 1H-1,4oxazino(4,3-a)indole nucleus are disclosed. The amino portion of the amino(lower)alkyl radical may be further substituted with one or two lower alkyl groups or incorporated in a heterocyclic amino radical. The derivatives are substituted further at positions 1 and 10 and may be optionally substituted at positions 3, 4, 6, 7, 8 and 9. The oxazinoindole derivatives of this invention are useful antidepressant and antiulcer agents. Methods for the preparation and use of these derivatives are also disclosed.

United States Patent Demerson et al.

[ 5 Oct. 7, 1975 OXAZINOINDOLE- AND TI-IIAZINOINDOLE DERIVATIVES [73]Assignee: Ayerst, McKenna and Harrison Ltd., Montreal, Canada [22]Filed: June 19, 1974 [21] Appl. No; 480,997

Related US. Application Data [62] Division of Ser. No. 226,287, Feb. 14,1972, Pat. No.

[52] US. Cl 260/243 R; 260/244 R; 424/246; 424/248 [51] Int. Cl. C07D279/14; C07D 265/28 [58] Field of Search 260/243 R, 244 R [56]References Cited UNITED STATES PATENTS 3,532,7l9 lO/l970 Theimer260/3452 3,833,575 9/l974 Demerson et al 260/243 R FOREIGN PATENTS ORAPPLICATIONS 2,051,496 4/l97l Germany OTHER PUBLICATIONS Rieche et al.,Synthetic Methods of Organic Chemistry, Vol. l2, p. 36l, S, Karger(pub), New York (1958) Warren et a]., Synthetic Methods of OrganicChemistry," Vol. [3, pp. 36l-362, S. Karger, pub., New York l959).

Primary ExaminerJohn M. Ford Attorney, Agent, or Firm-John P. FloydABSTRACT Oxazionindole derivatives characterized by having anamino(lower)alkyl radical attached to the l position of alH-l,4-oxazino[4,3-a]indole nucleus are disclosed. The amino portion ofthe amino(lower)alkyl radical may be further substituted with one or twolower alkyl groups or incorporated in a heterocyclic amino radical. Thederivatives are substituted further at positions 1 and I0 and may beoptionally substituted at positions 3, 4, 6, 7, 8 and 9. The oxazinoindole derivatives of this invention are useful antidepressant andantiulcer agents. Methods for the preparation and use of thesederivatives are also disclosed.

22 Claims, No Drawings OXAZINOINDOLE- AND THIAZINOINDOLE DERIVATIVESThis is a division of application Ser. No. 226,287, filed Feb. 14, l974,now US. PaL No. 3,833,575.

BACKGROUND OF THE INVENTION 1. Field of Invention This invention relatesto novel oxazinoindole and thiazinoindole derivatives, to processes fortheir preparation and to intermediates used in these processes. Forconvenience, further reference in this specification will be made tothese compounds as oxazinoindole derivatives.

More specifically, the present invention relates to oxazinoindolederivatives possessing valuable pharmacologic properties. For example,these derivatives exhibit useful antidepressant properties at dosageswhich do not elicit undesirable side effects. Furthermore the presentderivatives exhibit properties useful for the treatment and preventionof ulcers. The combination of these pharmacologic properties togetherwith a low order ot toxicity render the oxazinoindoles of the inventiontherapeutically useful.

2. Description of the Prior Art Very little attention has been given to1,4- oxazino[4,3-a]indole derivatives prior to this disclosure. In thefew reports that do exist, such as the reports, by .l. A. Elvridge andF. S. Spring, 1. Chem. Soc., 2935 (I949) and W. R. Smith and R. Y. Moir,Can. J. Chem, 30, 4ll (1952), the oxazinoindole derivatives are treatedmore in the manner of chemical curiosities. ln these instances, theoxazinoindoles are distinguished readily from the compounds of thisinvention by having the pyran portion of their ring system at a higheroxidation state.

SUMMARY OF THE INVENTION The oxazinoindole derivatives of this inventionare characterized by having an amino(lower)alkyl radical attached to alH-l,4-oxazino[4,3-a]indole nucleus. The preferred derivatives of thisinvention are represented by formula I,

in which R is lower alkyl or lower cycloalkyl; R, R, R and R are thesame or different selected from the group consisting of hydrogen orlower alkyl; R is hydrogen, lower alkyl, hydroxy, lower alkoxy, loweralkanoyloxy, nitro or halo, R is lower alkyl; X is oxy or thio; andAlk-NR"R is an amino(lower)alkyl radical in which Alk is an alkyleneselected from the group consisting of CR R", CRR"CR' R,CRIORHCRHRHJCRHRIIS d CRIURIICRIERILICRIJRIECRHIRIT R10 R11 R12 R', R RR and R are hydrogen or lower alkyl, and R and R are either the same ordifferent selected from the group consisting of hydrogen and loweralkyl, or R and R together with the nitrogen atom to which they arejoined form a heterocyclic amine radical selected from the groupconsisting of l-pyrrolidinyl, piperidino, morpholino, piperazino,4-(lower alkyl)-lpiperazinyl and 4-[hydroxy(lower)alkyl l -piperazinyl.

DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl" as usedherein contemplates straight chain alkyl radicals containing from one tosix carbon atoms and branched chain alkyl radical containing up to fourcarbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, Z-methylpentyl and the like.

The term lower cycloalkyl as used herein contemplates saturated cyclichydrocarbon radicals containing from three to six carbon atoms andincludes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term lower alkoxy" as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy, ethoxy, isopropoxy, t-butoxy and the like.

The term lower alkanoyloxy" as used herein contemplates both straightand branched chain alkanoyloxy radicals containing from two to sixcarbon atoms and includes acetoxy, propionyloxy, pivaloyloxy.hexanoyloxy and the like.

The term halo as used herein contemplates halogens and includesfluorine, chlorine, bromine and iodine.

The compounds of formula I are capable of forming acid addition saltswith pharmaceutically acceptable acids. Such acid addition salts areincluded within the scope of this invention.

The acid addition salts are prepared by reacting the base form of theappropriate compound of formula I with either one or two equivalents,depending on the number of basic nitrogens in the compounds, orpreferably with an excess of the appropriate acid in an organic solvent,for example, ether or an ethanol-ether mixture. These salts, whenadministered to mammals, possess the same pharmacologic activities asthe corresponding bases. For many purposes it is preferable toadminister the salts rather than the base compounds. Among the acidaddition salts suitable for this purpose are salts such as the sulfate,phosphate, lactate, tartrate, maleate, citrate, hydrobromide andhydrochloride. Both the base compounds and the salts have the distinctadvantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochcmical isomers of thecompounds of formula I which result from asymmetric centers, containedtherein. These isomeric forms may be prepared by different methods andare purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractionalcrystallization of the diastereoisomeric salts formed thereof, forinstance, with dor 1 tartaric acid or D-(+)a-bromocamphor sulfonic acid,are also included.

Antidepressant Activity The useful antidepressant activity of thecompounds of formula I and their acid addition salts withpharmaceutically acceptable acids may be demonstrated in standardpharmacologic tests, such as, for example, the tests described by F.Hafliger and V. Burckhart in Psychopharmacological Agents", M. Gordon,Ed., Academic Press, New York and London, l964,pp. 75 83. Morespecifically, as noted in the latter reference the antidepressantproperties of a compound may be demonstrated by its capacity toantagonize the depressant effects of reserpine. Furthermore, it is welldocumented that reserpine in animals products a model depression whichcan be used for detecting antidepressant properties. Accordingly, thecompounds of the present invention antagonize reserpine effects in miceat doses ranging from about 1 to 100 mg/kg. Several of the preferredcompounds, for instance. 1, l O-dimethyll -[2-( ethylamino )ethyl]-3,4-dihydrolH-l .4-oxazino[4,3-a]indole hydrobromidc (Example 284),1,l0-dimethyl-l-[(2-dimethylamino)ethyl]-3,4- dihydrol H-l,4-oxazino[4,3-a] indole hydrochloride (Example 284), l-( 3-aminopropyll l 0-dimethyl-3,4-dihydrol H- l ,4- oxazino-[4 3-a]indole hydrochloride(Example 286), l,l0-dimethyll 3-(methylamino)propyl]-3,4- dihydrol H-l,4-oxazino[4,3-a]indolc hydrochloride (Example 285) and l, l O-dimethyll3-(dimethylamino )propyl ]-3,4-

dihydrol H- l ,4-oxazino[4,3-a]indole hydrochloride (Example 287),antagonize the effects of reserpine in mice at dose ranges from about Ito l0 mg/kg.

When the compounds of this invention are used as antidepressants inwarm-blooded mammals, e.g. rats and mice, they may be used alone or incombination with pharmacologically acceptable carriers, the proportionof which is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard biologicalpractice. For example, they may be administered orally in solid formcontaining such excipients as starch, milk sugar, certain types of clayand so forth. They may also be administered orally in the form ofsolutions of they may be injected parenterally. For parenteraladministration they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitiated with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. In general,the compounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in a range of from about 0. l mg to about 50 mg per kiloper day, although as aforementioned variations will occurfHowever, adosage level that is in the range of from about 0.5 mg to about 25 mgper kilo per day is most desirably employed in order to achieveeffective results.

Antiulcer Acticity The compounds of formula I of this invention possessanother useful pharmacologic property; that is, they are usefulantiulcer agents. More particularly, the said compounds of thisinvention exhibit antiulcer activity in standard pharmacologic tests,for example, the test described by D. A. Brodie and L. S. Valitski,Proc. Soc. Exptl. Biol. Med., 1 I3, 998 (1963), based on the preventionof stress-induced ulcers.

When the compounds of formula I are employed as antiulcer agents, theymay be formulated and administered in the same manner as described abovefor their use as antidepressant agents.

Processes For the preparation of the oxazinoindoles of this invention weprefer to use as starting materials the compounds of formula II,

in which R and R are as defined in the first instance.

The starting materials of formula II are either well known, for example,skatole and 3-ethylindole, or they may be prepared from indole or knownindole derivatives, for example, see P. L. Julian, et al., HeterocyclicCompounds", R. C. Elderfield, Ed., Vol. 3, John Wiley and Sons, Inc.,New York, 1952, p. 1, according to the method of R. Robinson, et al.,described in US. Pat. No. 2,407,452, issued Sept. 10, I946.

The starting material of formula ll is then converted to the keyintermediate of formula III,

I 11mm in which R R", R, R R and R are as defined in the first instanceand X is hydroxy or mercapto.

This conversion may be effected by several methods. One general methodinvolves reacting the appropriate lithium derivative of the startingmaterial of formula ll with ethylene oxide or an appropriate lower alkylsubstituted ethylene oxide to afford the desired intermediate of formulaII] in which X is hydroxy. The desired intermediates may also beobtained by treating the appropriate starting material of formula llwith the appropriate ethylene oxide derivative according to theprocedure of M. Julia, et a]., Bull. Soc. Chim. Fr., 2291 i966).

The lower alkyl substituted ethylene oxides are prepared by knownmethods; for example, see V. Franzen and H. E. Driesen, Chem. Ber., 96,l88l (1963).

An alternative method for the preparation of intermediates of formula11] in which R and R are hydrogen involves treating the startingmaterial of formula II with an a-haloacetic acid lower alkyl ester offormula LCRR"COO (lower alkyl) in which L is halo and R and R are asdefined in the first instance, in the pres ence of a suitable protonacceptor and using preferably an inert solvent for the reaction. Thea-haloacetic acid lower alkyl esters are well known, for example seeRodds Chemistry of the Carbon Compounds", S. Coffey, Ed., Vol. lc, 2nded, Elsevier Puboishing Co., Amsterdam, 1965, pp. 20l 205. Suitableproton acceptors include sodium hydride, alkali metal carbonates andtriethylamine. Suitable inert solvents include tetrahydrofuran, benzene,toluene and dimethylformamide. Preferred conditions for the N-alkylationinclude the use of sodium hydride as a proton acceptor andtetrahydrofuran as an inert solvent. Although the optimum temperatureand reaction time will vary de pending on the reactants employed, thereaction is generally performed at the boiling point of the reactionmixture for a period of 30 minutes to 48 hours.

The indole-l-acetic acid lower alkyl ester derivative obtained by theabove N-alkylation reaction is thereafter hydrolyzed, preferably with asolution of potassium hydroxide in methanol water, to give thecorresponding indole-l-acetic acid derivatives which on reduction withlithium aluminum hydride affords the desired intermediate of formula Illin which R and R are hydrogen and X is hydroxy.

Again alternatively, the latter indole-l-acetic acid derivative may alsobe reacted with two equivalents of a lower alkyl Grignard reagent, forexample, methyl magnesium bromide, to give, after hydrolysis of themagnesium-halogen derivative, the desired intermediates of formula lll(R R lower alkyl and X hy droxy), see L. F. Fieser and M. Fieser,Advanced Organic Chemistry, Reinhold Publishing Corp. New York, l96l, p.272.

When the corresponding intermediates of formula III in which X ismercapto are desired, a procedure similar to that described by N. N.Suvorov and V. N. Buyanov, Khim.-Farm. ZH., l, (l967), [Chem. Abstr. 67.73474a l967)], for converting 3-( 2-bromoethyl)- indole toindole-3-ethanethiol, may be employed. More particularly, the aboveintermediate of formula III in which X is hydroxy is treated withphosphorus tribromide in an inert solvent, for example, ether or carbontetrachloride, followed by treatment of the product with sodium orpotassium thiosulfate to afford the corresponding sodium or potassiumB-( l-indolyl)ethyl thiosulfate derivative, respectively. Treatment ofthe latter product with strong alkali, for example, sodium or potassiumhydroxide, yields the corresponding bis- [w-(indolyl)ethyl]disulfidederivative. Finally reduction of the latter compound with lithiumaluminum hydride gives the desired intermediate of formula III in whichX is mercapto.

Alternatively, the starting materials of formula III in which R and Rare hydrogen and X is mercapto may be prepared by oxidizing thecorresponding intermediate of formula III in which X is hydroxy,described above, with N,N-dicyclohexylcarbodiimide and dimethylsulfoxide in the presence of a suitable acid, for example,trifluoroacetic acid, see K. E. Pfitzner and J. G. Moffat, J. Amer.Chem. Soc., 87, 5670 l965), to give the corresponding aldehydederivative. The same aldehyde derivative may also be obtained by N-alkylation of the appropriate starting material of formula ll with anappropriate a-halo-acetaldehyde derivative (see Rodds Chemistry of theCarbon Compounds", cited above, Vol,, lc, pp. 24 26) according to theconditions described above for N-alkylation with a-haloacetic acid loweralkyl esters.

The latter aldehyde derivative is converted to its correspondinggem-dithiol derivative with hydrogen sulfide, which is reduced withlithium aluminum hydride, according to the method of T. L. Cairns, etal., J. Amer. Chem. Soc., 74, 3982 1952), to yield the desired startingmaterial of formula lll.

It should be noted that the preceding processes may not be entirelypractical for the prepparation of the compounds of formula III in whichX is hydroxy or mercapto and R is hydroxy or lower alkanoyloxy. For thisreason, the preferred starting materials of formula ll for the ultimatepreparation of the compounds of formula l in which R is hydroxy or loweralkanoyloxy are the corresponding compounds of formula ll in which R isbenzyloxy, Le. a hydroxyl with a protecting benzyl group or othersuitable protecting group (see J. F. W. McOmie, Advances in OrganicChemistry", Vol. 3, R. A. Raphael, et al., Ed., lnterscience Publishers,New York, I963, pp. 191 294). After the appropriate transformationsdescribed below, the benzyloxy group is removed by hydrogenation, in thepresence of a catalyst, for example, 10% palladium on carbon, just priorto affording the desired corresponding compound of formula I in which Ris hydroxy. The latter may be converted if desired to the correspondingcompound of formula I in which R is lower alkanoyloxy by conventionalmeans, for example, by treatment with the ap propriate lower alkanoicanhydride preferably in the presence of pyridine.

The above described intermediate of formula III in which R R", R R, R, Rand X are as defined in the first instance are now subjected to a keyreaction comprising the treatment of said starting materials with acompound of formula in which R is as defined in the first instance and Zis selected from the group consisting of:

a. COOR and Alk COOR in which R'" is hydrogen or lower alkyl and Alk isan alkylene selected from the group consisting of CR' R, CRIORHCRIZRIZSd CRHIRIICRI2R13CR14R15 wherein R'", R", R", R, R and R are hydrogen orlower alkyl,

b. C()l\lR"R and AlkCONR"R in which Alk, R"

and R are as defined above,

0. CH OCOR and AlkCH OCOR in which R is hydrogen or lower alkyl and Alkis as defined above,

d. Alk L in which Alk is an alkylene selected from the group consistingof CR R CHR cR R cR R CHR and CRRCR' R CRR CHR wherein R, R, R, R, R, Rand R are as defined above and L is halo,

e. Alk NR*COR in which Alk and R are as defined in the first instanceand R is hydrogen or lower alkyl containing from one to five carbonatoms, and

f. Alk-N0 in which Alk is as defined in the first instance, in thepresence of an acid catalyst to yield the compounds of formula V inwhich R, R R, R, R R", R", X and Z are as defined above.

111 lime-9x n Thereafter the appropriate compound of formula V isconverted to the desired oxazincindole of formula I according to theprocesses described hereinafter.

In practising the condensation (11] Vl V) we have found it preferable touse a solvent as a reaction medium. Any solvent inert to the reactionconditions may be used. Suitable solvents include aromatic hydrocarbons,for example, benzene or toluene, ethers and cyclic ethers, for example,diethyl ether, dioxan or tetrahydrofuran, halogenated hydrocarbons, forexample methylene dichloride or carbon tetrachloride and the like.Benzene and toluene are especially convenient and practical for thisuse. A variety of suitable acid catalysts may be used for thiscondensation, for example, the type of catalyst used in a Friedel-CraftsReaction, i.e. p-toluenesulfonic acid, aluminum chloride, phosphoruspentoxide, boron trifluoride, zinc chloride, hydrochloric acid,perchloric acid, trifluoroacetic acid, sulfuric acid and the like.p-Toluenesulfonic acid, aluminum chloride, boron trifluoride andphosphorus pentoxide are included among the preferred acid catalysts.The amount of acid catalyst used is not especially critical and mayrange from 0.0] molar equivalents to 100 molar equivalents; however, arange of from 0.! to molar equivalents is generally preferred. The timeof the reaction may range from it) minutes to 60 hours, with thepreferred range being from one-half to 24 hours. The temperature of thereaction may range from C'. to the boiling point of the reactionmixture. Preferred temperature ranges include 20 to 120C.

A more detailed description of the preparation of the above intermediatecompounds of formula V and a description of their subsequent conversionto the oxazinoindole derivatives of formula I are disclosed below. Forconvenience these descriptions are catagorized into sections accordingto the group selected for Z for the intermediate.

a. Preparation and Conversion of Intermediates of Formula V (Z COOR" andAlkCOOR intermediates of formula V (Z COOR and Alk COOR in which R" ishydrogen or lower alkyl and Alk is as defined in the first instance andR, R R R, R, R, R and X are as defined in the first instance) arereadily obtained by the condensation (lll lV V) by using ketoacid orketoesters of formula i Rail in which R 1 is as defined in the firstinstance and Z is COOR" or Alk COOR" as defined above together with theintermediate of formula [I].

Generally comparable yields of product are obtained in this process wheneither the ketoacid or the corresponding ketoester is used. However, inthe case where it is desired to prepare an acid compound of formula V inwhich Z is ALKCOOR wherein Alk is CR R and R is hydrogen (i.e., an acidintermediate of formula V), it is preferable to first condense theappropriate B-ketoester of formula IV rather than the correspondingBFketoacid and then hydrolyze the resulting ester product to give thedesired acid compound.

Moreover, in the general practice of this invention it is often moreconvenient to prepare the acid compounds of formula V by using theketoester instead of the ketoacid in this process and then hydrolyze theresulting ester product to the desired acid, the reason being simplythat the ketoesters are generally more readily available eithercommercially or by synthesis.

Compounds of formula V in which Z is COOR" or AlkCOOR wherein Alk is asdefined in the first instance and R is lower alkyl, i.e. esterintermediates of formula V, are hydrolyzed readily to theircorresponding acids of formula V by treatment with a suitable alkali,for example, potassium hydroxide or sodium carbonate, in aqueousmethanol or aqueous ethanol or be treatment with lithium iodide in asuitable organic solvent, for example, collidine, see L. F. Fieser andM. Fieser, Reagents for Organic Synthesis", John Wiley and Sons, Inc.,New York, 1967, pp. 6l5 617.

The 01-, [3-, 7-, and 8-ketoacids and -ketoesters of formula Ill areeither known, for example, ethyl pyruvate, levulinic acid, ethyla,a-dimethylacetoacetate and Bfi-dimethyllevulic acid or they may beprepared by known methods described in general organic chemistrytextbooks. For example, a comprehensive review on the properties andpreparation of such a-, 3-, 'yand S-ketoacids and -ketoesters may befound in "Rodds Chemistry of the Carbon Compounds, cited above, Vol. Id,pp. 226 274.

Thereafter these intermediate acids and esters of formula V areconverted to compounds of formula I in which R, R R, R, R R, R and X areas defined in the first instance and -Alk-NR R is an amino(lower)alkylin which Alk is CH or Allt'CH wherein Alk is as defined in the firstinstance and R and R are as defined in the first instance.

in the case where the acid intermediate of formula V is employed, saidacid is subjected to admidation by treatment with a lower alkylchloroformate, preferably ethyl chloroformate, in the presence oftriethylamine, affording the corresponding mixed anhydride, which isconverted by treatment with the appropriate amine of formula HNRR inwhich R and R are as defined in the first instance, for example,ammonia, methylamine or dimethylamine, to yield the corresponding amideof formula V in which Z is CONRR or Alk'CONRR wherein Alk, R and R areas described in the first instance.

Alternatively, the latter amides are also obtained by treating the esterintermediates of formula V, described above, with the appropriate amineaccording to known amidation methods, for example, see A. L. F. Beckwithin The Chemistry of Amides", .I. Zalicky, Ed., Interseience Publishers,New York, I970, pp. 96 l05.

Thereafter, the amides so obtained are reduced with a suitable complexmetal hydride to yield the desired oxazinoindoles. Examples of suitablecomplex metal hydrides are lithium aluminum hydride, lithium aluminumhydride-aluminum chloride, aluminum hydridealuminum chloride, diboraneand sodium borohydridealuminum chloride. Lithium aluminum hydride is preferred.

Two aspects of this latter reduction of the amides are worth noting. Thefirst aspect relates to the reduction of the above amides of formula Vin which Z is CONR*R or Alk-CONR"R wherein Alk is as defined in thefirst instance, R is hydrogen and R is lower alkyl, i.e. secondaryamides, to their corresponding oxazinoindolcs of formula I, i.e.secondary amines. In this case a modification of the above process inthe following manner is among the preferred procedures. Theaforementioned acid or ester intermediate of formula V is reacted withan amine of formula NHR R in which R" is benzyl and R is lower alkylcorresponding to the R of the desired amine. This step is performedaccording to the amidation step described above. The resulting amide isthen reduced with a complex metal hydride according to the aboveprocedures. Thereafter the benzyl groupis removed by hydrogenolysis inthe presence of a catalyst, preferably palladium on carbon, to affordthe desired secondary amine compounds of formula I.

The second aspect relates to a more general modification for thereduction of the above amides of formula V in which Z is CONRR orAlk-CONR R wherein Alk', R", and R is as defined in the first instance.

This modification is applicable to the reduction of the tertiary,secondary and primary amides and is a preferred modification for thereduction of the latter two. In practising this modification, theaforementioned amide of formula V is treated with triethyloxoniumfluoroborate, see R. F. Borch, Tetrahedron Letters, No. I, 61 I968), ordimethyl sulfate, see H. Bredereck, et al., Chem. Ber., 98, 2754 (I965),in an inert solvent, for example, methylene dichloride, whereby thecorresponding iminoether fluoroborate or methyl sulfate salt isobtained, respectively. Subsequent reduction of the salt thus obtainedwith a complex metal hydride according to the procedure described abovefor reducing amides yields the desired oxazinoindole of formula 1.Alternatively, the above fluoroborate or methyl sulfate salt derivedfrom a secondary or primary amide may be decomposed by base treatment,for example, with 10% sodium hydroxide solution or triethylamine, togive the corresponding iminoether derivative which is then reduced in alike manner to the desired oxazinoindole.

When applying the aforementioned steps in the preparation of compoundsof formula I in which R is hydroxy or lower alkanoyloxy, it ispreferable to use corresponding intermediates in which R is benzyloxyfollowed by the appropriate transformations as noted previously to yieldthe desired compounds of formula I.

b. Preparation and Conversion of Intermediates of Formula V (Z CONRR andAIkCONR R The intermediates of formula V in which Z is cONR R andAlkCONR R wherein R, R and Alk are as defined in the first instance,described in the previous section, are also obtained directly byutilizing the appropriate starting materials of formula III and a-, [3-,'y-, or B-ketoamides of formula in which R is as defined above and Z isCOI\IR"R or Alk'CONR"R in which Alk', R and R are as defined above. Theketoamides required for this condensation are either known, for example,pyruvamide or a,a-dimethylacetoacetamide, or they may be prepared byknown methods, for instance, see Rodd's Chemistry of the CarbonCompounds", cited above, Vol. ld, pp. 226 274.

Thereafter these amides of formula V are converted by the reductionprocess, described above, to the compounds of formula I in which R, R R,R, R R", R

and X are as defined in the first instance and Alk- NRR isamino(lower)alkyl in which Alk is CH or AlkCH wherein Alk is as definedin the first instance and R and R are as defined in the first instance.

c. Preparation and Conversion of lntermediates of Fomiula V (Z CH OCORand Alk'CH OC0R' lntermediates of formula V in which Z is CH O- COR andAlkCH OCOR" in which Alk and R are as defined in the first instance, areobtained when a starting material of formula III is condensed with aketoalcohol lower alkanoic acid ester of formula RCOCH OCOR or R'COAIkCHOCOR in which R Alk and R are as defined in the first instance in thepresence of a suitable acid catalyst according to the conditionsdescribed above for the condensation (III IV V). The ketoalcohol loweralkyl esters are either known, for example, acetonyl acetate orS-acetoxy-pentan-Z-one, or may be prepared by known methods, forinstance, see Rodd's Chemistry of the Carbon Compounds", cited aboveVol. Id, pp. 49 54.

These intermediates of formula V may then be utilized for thepreparation of compounds of formula I of this invention in the followingmanner. The intermediate is hydrolyzed with an aqueous alcoholicsolution of a suitable alkali, for example, sodium hydroxide in aqueousmethanol to afford the corresponding primary alcohol. It should be notedthat the latter primary alcohols may also be obtained by the directreduction of the intermediate acids and esters of formula V, describedherein in section (a), using a suitable complex metal hydride asdescribed therein. The primary alcohol is then oxidized to thecorresponding aldehyde. Although a variety of methods are known for theoxidation of a primary alcohol to its corresponding aldehyde, see forexample, Rodds Chemistry of the Carbon Compounds, cited above, Vol. lc,pp. 4 10, we have found that the method of K. E. Pfitzner and J. G.Moffat, J. Am. Chem. Soc., 87, 5670 I965), usingN,N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of asuitable acid, for example, trifluoroacetic acid, is both efficaciousand convenient. Thereafter the aldehyde is reacted with an amine offormula HNR R in which R and R are as defined in the first instanceaccording to the method of K. N. Campbell, et al., J. Amer. Chem. Soc.,70, 3868 1948) in the case when the amine used is ammonia or a primaryamine, or according to the method of N. J. Leonard and J. V. Paukstelis,J. Org. Chem., 28, I397 (1963) when the amine is a secondary amine, togive the corresponding Schiff base or immonium salt, respectively. Theproduct so obtained is reduced with sodium borohydride, see E. Schenker,Angew. Chem., 73, 8| (I961), to yield compounds of formula I in which R,R R", R R, R, R and X are as defined in the first instance Alk-NR"R isan amino(lower)alkyl in which Alk is Chg or Alk'Cl-I2 wherein Alk is asdefined in the first instance and R and R are as defined in the firstinstance.

Alternatively, the latter compounds of formula I may be obtained byconverting the above corresponding alcohol to a reactive intermediatesuch as the corresponding halide, mesylate or tosylate, which may thenbe reacted with two or more molar equivalents or an amine of formula HNRR" in which R and R are as defined in the first instance. Preferablythis reaction is performed in a suitable inert solvent, for example,tetrahydrofuran, at 40 to 100C. or at the boiling point of the reactionmixture for a period of eight to 24 hours. In connection withalkylations of amines of formula HNR"R in which R is hydrogen and R islower alkyl as disclosed herein, it is generally more advantageous withrespect to yields to perform the alkylation with the correspondingNbenzyl derivative if said amine, i.e., an amine of formula HNRR inwhich R is benzyl and R is lower alkyl. Thereafter, when all appropriatetransformation have been performed, the N- benzyl group may be removedby hydrogenolysis with a catalyst, preferably palladium on carbon, togive the desired compounds of formula 1.

Alternatively, the above aldehyde is oxidized with a suitable oxidizingagent to yield the corresponding acid intermediates of formula Vdescribed in section (a). Although a variety of suitable oxidizingagents may be used for this purpose, for example, silver oxide, alkalinepermanganate, hydrogen peroxide, the use of silver oxide according tothe method of M. Delepina and P. Bennet, Compt. rend., l49,39 (1909) ispreferred.

Again alternatively, the above aldehyde is converted to its oxime whichon reduction with a complex metal hydride yields the correspondingprimary amine of formula l in which R, R R, R R", R, R and X are asdefined in the first instance and -Alk-NR"R" is an amino(lower)alkyl inwhich Alk is CH, or Alk-CH wherein Alk is as defined in the firstinstance and R and R" are hydrogen.

In turn these latter compounds of formula I may be further N-alkylatedon the nitrogen of the primary amine with the appropriate lower alkylhalide to the corresponding compounds of formula I in which Y is-Alk-NRR wherein Alk is CH; or AlkCl-l wherein Alk is as defined in thefirst instance and R- is hydrogen or lower alkyl and R is lower alkyl(i.e. aecondary or tertiary amines). In this case depending on theparticular derivative desired the N-alkylation may be effected with oneor two moles of the alkyl halide to give respectively the secondary ortertiary amine. On the other hand the N-Alkylation may be effected intwo steps introducing a different alkyl group each time to afford thecorresponding tertiary amine in which R and R are different loweralkyls.

When it is desired to prepare the above tertiary amine compounds inwhich R or R are either or both methyl, an alternative alkylation methodcomprises reacting the appropriate corresponding primary or secondaryamine with an aqueous mixture of a substantial excess of formaldehydeand formic acid according to the conditions of the Eschweiler-Clarkereaction, see M. L. Moore, Organic Reactions, 5, 30l I949), wherebyN-methylation is efi'ected.

Another N-alkylation method which may be applied to the above primaryand secondary amines involves acylation with a lower alkanoic anhydrideor acid halide and subsequent reduction of the resulting amide.

Furthermore, the above primary amines may be used to preparecorresponding compounds of formula I in which R" and R" together withthe nitrogen atom to which they are joined form a heterocyclic amineradical as defined in the first instance. When used in this manner theprimary amines are subjected to known N- alkylation methods, forexample, see Method J described by R. B. Moffet, J. Org. Chem., 14, 8621949), with the appropriate a,m-dibromides, for example, tetramethylenedibromide, pentamethylene dibromide, bis( 2-chloroethyl )ether, bis(2-chloroethyl )benzylamine followed by hydrogenation in the presence of10% palladium on carbon to remove the protecting S benzyl group, abis(2-chloroethyl) lower alkylamine or abis('Z-chloroethyl)-N-[hydroxy(lower)alkyllamine, to give thecorresponding desired compound of formula l in which R and R togetherwith the nitrogen atom to which they are joined form a heterocyclic l0amine radical, i.e. a pyrrolidino, piperidino, morpholino, piperazino,4-(lower)alkyl-l-piperazinyl or 4- [hydroxy( lower)alkyl l -piperazinylrespectively.

d. Preparation and Conversion of intermediates of 15 Fomtula V (Z Alk L)Intermediates of formula V in which Z is Alk L wherein All: and L are asdefined in the first instance, are obtained when a starting material offormula III is condensed with a B, y or S-haloketone of formula RCOAlk-L in which R, Alk and L are as defined in the first instance in thepresence of a suitable acid catalyst according to the conditionsdescribed above for the condensation (Ill [V V). The haloketones areeither known, for example, 4-chlorobutan-2-one, or

they may be prepared by known methods, for instance, see Roods Chemistryof Carbon Compounds", cited above, Vol. lc., pp. 70 7l and Methoden derOrganischen Chemie", Houben-Weyl, E. Muller, Ed, Vol V/3, Georg ThiemeVerlag, Stuttgart 1962, pp. 511

Thereafter these intermediates of formula V are treated with a two molarexcess of an amine of formula HNR"R in which R and R are as defined inthe first instance to yield the compounds of formula 1 in which R, R, R,R, R, R, R" and x are as described in the first instance, and -AlkNR"R"is an amino(lower)alkyl in which Alk is Alk as defined in the firstinstance and R and R are as defined above. Preferably this reaction isperformed in a suitable inert solvent, for example, tetrahydrofuran atthe boiling point of the reaction mixture for a period of 8 to 24 hours.

c. Preparation and Conversion of Intermediates of Formula V (Z AlkNRCOR)in which R, Alk, R" and R are as defined in the first instance togetherwith the appropriate starting material of formula III.

The ketoamides used herein are either known, for example,formamidoacetone IA, Treibe and W. Sutter, Chem. Ber., 84, 96 l95l )1,see also R. H. Wiley and O. H. Borum, J. Amer. Chem. Soc., 70, 2005(l948), or may be prepared by known procedures, for example, seeMethoden der Organischen Chemie", cited above, Vol. Xl/l, 1957,especially pp. 58 62, 285 289 and 508 509, and F. F. Blicke, OrganicReactions, l, 303

Thereafter, reduction with a complex metal hydride converts the instantintermediates of formula V to oxazinoindoles offormula l in which R, RR, R, R R, R and X are as described in the first instance, and AlkNRR"is an amino(lower)alkyl in which Alk and R are defined in the firstinstance and R is lower alkyl.

f. Preparation and Conversion of Intermediates of Formula V (Z Alk NIntermediates of formula V in which Z is AlkNO wherein Alk is as definedin the first instance, are ob tained by the condensation (III IV V) whenthe starting materials of formula III and appropriate a-, 13-, 71-, andfi-nitroketones of formula in which R and Alk are as defined in thefirst instance are employed therein in the presence of a suitable acidcatalyst. In this case trifluoroacetic acid is the preferred acidcatalyst.

The nitroketones used herein are either known, for example,l-nitro-2-propanone, N. Levy and C. W. Scaife, J. Chem. Soc., 1 100,l946) and -nitro-2- hexanone, H. Shechter, et al., J. Amer. Chem. Soc.74, 3664 1952) or they may be prepared by known methods, for example,see Levy and Scaife, cited above, Shecter, et al. cited above, RoddsChemistry of Carbon Compounds, cited above, Vol. lc, pp. 7l 72 andMethoden der Organischen Chemie", cited above, Vol. X/l, 1971, p. 203.

Thereafter, these intermediates of formula V are reduced with a complexmetal hydride, preferably lithium aluminum hydride, to afford theoxazinoindoles of formula I in which R, R R R R R, R and X are asdefined in the first instance, and Alk-NR*R is an amino(lower)alkyl inwhich Alk is defined in the first instance and R and R are hydrogen.

If desired the latter compounds may be N-alkylated according to themethods described in section (e) to give the compounds of formula I inwhich R, R R R R R, R and X are as defined in the first instance andAlk--NRR is an amino(lower)alkyl in which Alk, R and R are as defined inthe first instance.

The following examples illustrate further this invention.

EXAMPLE l 3-Methylindole-l-ethanol(lll: R R R, R and R H R= CH;, and XOH) Procedure A:

Commercial n-butyl lithium in hexane (3.05 mole) is diluted with 1000 mlof dry tetrahydrofuran (THF). To this cooled (10 to 0C) solution thestarting material of formula II, skatole (393 g, 3.0 mole) in 1000 ml ofdry THF, is added dropwise. The reaction is stirred at the same lowtemperature for l hour and then 300 ml of ethylene oxide in 300 ml ofdry THF is added to the mixture. The temperature of the reaction isallowed to rise to room temperature and at this temperature the reactionis stirred overnight.

THF is evaporated and the residue is dissolved in methylene chloride andwashed with concentrated HCl. The methylene chloride solution is thenwashed with 10% sodium bicarbonate. water and dried LII (MgSO Thesolvent is evaporated and the product distilled at reduced pressure togive the title compound, b.p. l24C/0.25 mm.

Procedure B:

The starting material of formula II, skatole (35 g, 0.276 mole) in 300ml of dimethylformamide (DMF) is added dropwise to stirred mixture ofsodium hydride (l4.0 g, oil dispension) in 325 ml of DMF. The mixture isheated at 40C for 2 hours. After cooling in an ice-water bath ethylbromoacetate (ll6.5 g, 0.7 mole) is added dropwise keeping thetemperature below 20C. After the addition, stirring is continued for 5minutes, and then water added cautiously to destroy any excess hydride.The reaction mixture is partitioned between water and ether. The etherlayer washed with water, dried (MgSO and evaporated under reducedpressure.

The residue, 3-methyl-indole-l-acetic acid ethyl ester, is dissolved in900 ml of methanol, potassium hydroxide g) in 400 ml of l:l methanol-H Ois then added. The mixture is stirred at room temperature for P/z hours.The methanol is evaporated under reduced pressure. The residue isdiluted with water (800 ml) and extracted (3 with ether. Acidificationwith 6NHCl of the aqueous phase yields 3-methyl-indole-lacetic acid,m.p. l74-l76C.

The latter compound (47.5 g., 0.25 mole) in 1000 ml of ether is slowlyadded to a stirred mixture of lithium aluminum hydride (12.5 g) (0.32moles) in 700 ml of ether. The reaction is kept below l5C using anicewater bath. The reaction is stirred for 15 minutes after theaddition, the excess hydride destroyed with water, and the precipitatecollected. The ether filtrate is washed with water, dried over sodiumsulfate and evaporated under reduced pressure to afford an oil.Chromatography on silica gel using 15% ethylaeetate in benzene as eluantgives the title compound, identical with the product of procedure A.

By following the procedure A of Example I other indole- 1 -ethanolintermediates of formula III for example those listed in Examples 6 to55, may be prepared by the appropriate choice of the starting materialof formula II and ethylene oxide derivative. For example, by replacingskatole and ethylene oxide with equivalent amounts of3,7-dimethyl-indole, R. Robinson et al., cited above, and3,3-dimethyl-1,2-epoxybutane, V. Franzen and H. E. Driesen, cited above,respectively, a mixture of B-isopropyl-oz,3,7-trimethyl-indole-lethanoland a-isopropyl fifi,7-trimethyl-indole-lethanol, are obtained. Suchmixtures of positional isomers may be separated by fractionaldistillation, fractional recrystallization or chromatography. Likewise,the replacement of skatole with S-isopropylindole, R. Robinson et al.cited above, in procedure A of Example I yields3-isopropylindole-l-ethanol.

By following procedure B of Example I other indolel-ethano]intermediates of formula III in which R and R are hydrogen may beprepared by the appropriate choice of the starting material of formulaII and a-haloacetic acid lower alkyl ester of formula LCR*R COO(loweralkyl) in which L is halo and R and R are hydrogen or lower alkyl. Forexample, by replacing skatole and ethyl bromoacetate with equivalentamounts of 3-ethylindole, R. Robinson et al., cited above, and2,3-epoxybutane, F. G. Bordwell and P. S. Landis, J. Amer. Chem. Soc.,79, I593 1957), respectively, a,B-dimethyl-3ethyl-indole-l-ethanol isobtained. Likewise the replacement of skatole with 3- butylindole, R.Robinson et al., cited above, in the procedure B of Example 1 yields3-butylindole-l-ethanol.

EXAMPLE 2 3-Methylindolel -ethanethiol (1": H R, R, R and R" H, R CH;,and X SH) Procedure A:

N,N-dicyclohexylcarbodiimide (9.0 g] is added to a cooled, stirredsolution of 3-methylindole-l-ethanol (3.0 g) in 30 ml of dimethylsulfoxidebenzene (2:1) containing trifluoroacetic acid (0.6 ml) andpyridine l [2 ml). The reaction is stirred at room temperature undernitrogen for hours. The reaction mixture is now diluted with 300 ml ofether, followed by the dropwise addition of a solution of oxalic acid(3.78 g) in l 1 ml of methanol. After 30 minutes, water (300 ml) isadded and the insoluble material is collected. The organic phase iswashed with water (2X), 5% aqueous sodium bicarbonate (2X) and water(2X). After drying (MgSO the organic phase is evaporated to yield 3-methylindole-l-acetaldehyde. The latter compound is then converted toits corresponding gem-dithiol with hydrogen sulfide and reduced withlithium aluminium hydride according to the method of T. L. Cairns etal., J. Amer. Chem. Soc., 74, 3982 1952), to yield the titlecompound,y"""-"' 2570 cm- Procedure B:

To a stirred solution of 7.2 g of 3-methylindole-lethanol, described inExample 1, in 500 ml. ofdry ether (ice bath) is slowly added 1.2 ml ofphosphorus tribromide in 100 ml of dry ether. A dark red oily complexseparates. The reaction mixture is stirred 36-48 hours at roomtemperature, then decomposed with ice and water. The separatedether-layer is quickly washed with a 10% solution of sodium bicarbonateand with water again, dried over calcium chloride for 2 min., decanted,and dried over magnesium sulfate for 30 min. The filtrate is evaporatedyielding l-(2-bromoethyl)-3- methylindole.

A solution of 10.4 g. of sodium thiosulfate in 60 water of ater and 100ml. of ethanol is poured onto 8.6 g. of l-(2-bromoethyl)-3-methylindole.The reaction mixture is stirred and heated at reflux for 3.5 hr.,allowed to cool, and evaporated to dryness. The solid residue isdissolved in boiling ispropanol, dried with a hydrated alkali-aluminumsilicate (Molecular Sieves), and filtered. Chilling of the filtratecauses 6.4 g. of the sodium indolyethyl thiosulfate derivative toprecipitate. This material is collected by filtration and washed withether. The isolated intermediate is heated at reflux with a solution ofsodium hydroxide (9 g. of NaOH, 60 ml. of water, 140 ml. of ethanol) for3 hr. Ethanol is removed under reduced pressure, the aqueous residuediluted with water and extracted with three portions of ether. Combinedether extracts are washed with water, saturated brine solution, anddried over magnesium sulfate. The filtrate is evaporated, to yieldbis-[2-(3- methylindolel-yl )ethyl ]disulfide.

The latter product (1.4 g.) in 100 ml. of dry ether is dropped into astirred suspension of 600 mg. LiAlH in 80 ml. of dry ether. The reactionmixture is heated to reflux for 3 hr. and then kept for hr. at roomtemperature. Decomposition with 2.8 ml. of water is carried out in astream of nitrogen. After 60 min. of stirring, a white precipitate isfiltered off with suction, the cake was washed with ether, and thefiltrate dried over magnesium sulfate. The clear ether solution isevaporated to give the title compound.

By following procedure A or B of Example 2 other indole-l-ethanethiolintennediates of formula III, for example those described in Examples 57to 106 may be prepared by the appropriate choice of indole-l-ethanolintermediates of formula II]. For example, by replacing3-methy1indole-lcthanol with an equivalent amount ofB-isopropyl-a,3,7-trimethylindole- 1 -ethanol,B-isopropyl-a,3,7-trimethyl-indole-l-ethanethiol is obtained. Likewise,by replacing 3-methylindole-l-ethanol with an equivalent amount of3-isopropylindole-l-ethanol, 3-isopropylindolel -ethanethiol isobtained.

EXAMPLE 3 3,4-Dihydro-l,lO-dimethyl-lH-1,4-oxazino{4,3-a]indole-l-acetieacid (V; R and R CH R R, R, R and R H, X O and Z CH COOH).

A mixture of the intermediate of formula III, 3-methylindole-l-ethanol(26.5 g., 0.15 mole), described in Example 1, intoluene (600 ml.), ethyl acetoacetate (36 g., 0.20 mole) andp-toluenesulfonic acid (2.0 g.) is heated at reflux for 6 hr. using awater separator. The toluene solution is washed with water, 5%bicarbonate solution, and again with water. The solution is then driedover sodium sulfate and the solvent evaporated under reduced pressure togive an oil. The oil was subjected to chromatography on silica gel.Elution with 10% ethyl acetate in benzene and concentration of theeluate affords the ester, 3,4-dihydro-1,10-dimethyl-1l-l-1,4-oxazino[4,3-a]indole-l-acetic acid ethyl ester, as an oil, v,,.,,,""l725 cm.

Hydrolysis of this ester to the title compound is effected as follows:The ester (39.9 g.) is dissolved in 800 ml. of methanol containing 22.5g. of KOH in 20 m1. of water. After stirring for 5 hr. at C. and for 12hr. at room temperature, the solvent is evaporated under reducedpressure. The residue is taken into water and washed twice with ether,acidified with 6N HCl and extracted with ether. The ether solution iswashed once with water, dried (Na SO.,) and evaporated under reducedpressure to afi'ord a solid. The solid is recrystallized from petroleumether to afford the title compound, m.p. l38 139C, nar (CDCl 61.75 (s,3H), 2.86 and 3.18 (d, J 14.5 cps, 2H), 4.07 (m, 4H).

An equivalent amount of methyl acetoacetate may replace ethylaeetoacetate in the procedure of this Example. In this case,3,4-dihydro-l ,10-dimethyl-lH-l,4- oxazino[4,3-a]-indole-l-acetic acidmethyl ester is obtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethylacetoacetate in the procedure of this Example. In this case,3,4-dihydro-l,l0-dimethyl-lH-l ,4- oxazino(4,3-a]-indole-l-acetic acidpropyl ester is obtained as the ester.

EXAMPLE 4 1 ,l0-Dimethyl-3,4-dihydro-1H-l.4-oxazino[4,3-a]indole-l-propionic acid (V; R and R =CH R R, R, R and R H, X O and ZCH CH COOH) Procedure A:

A mixture of the intermediate of formula lll, 3- methylindolel-ethanol(29.7 g., 0. l 7 mole), described in Example 1, ethyl levulinatc (26.96g., 0.187 mole) and p-toluenesulfonic acid (2.25 g.) in dry benzene (650ml.) is refluxed with stirring for 12 hr. with hydrated akalialuminumsilicate (Molecular Sieves No. 4). The benzene solution is washed with5% aqueous NUHO31 followed by water. Concentrations of the solution gavea residue, which is passed through a silica gel column using l57r ethylacetate in benzene to afford the ester, 3,4-dihydro-l,IO-dimethyl-l H-l,4- oxazino[4,3-a]indole-l-propionic acid ethyl ester, as on oil,y",,,,,, 1730 cm.

This ester (4| .9 g.) is dissolved in 650 ml. of methanol containing 23g. of KOH in 50 ml. of water and heated at 50C. for 1 hr. The solvent isevaporated and the residue taken into water. The aqueous mixture iswashed with ether twice, acidified with 6N HCl and extracted three timeswith ether. The ether solution is washed once with water, dried overMgSO and evaporated, under reduced pressure to yield a solid. The solidis recrystallized from ethyl acetate-petroleum ether to give the titlecompound, m.p. l 15- 1 16C., nmr (CDCl 81.62 (s, 3H), 2.30 (m, 7H), 4.04(4H). 7.2l 7.52 (m, 4H), 10.93 (1H).

Procedure B:

A mixture of the intermediate of formula III, 5- methylindole-l-ethanol(500 mg.), levulinic acid (580 mg.), 75 ml. of benzene, 1.7 g. ofphosphorus pentoxide and about 0.5 g. of diatomaceous earth (Celite) is25 stirred magnetically at room temperature for IS min. and then at 70C.for l A hr. The reaction mixture is filtered. The filtrate is washedthree times with 5N NaOH; the combined aqueous phase is washed twice 10mula V in which R, R R R, R R, R, X are as defined in the first instanceand Z is COOR or Alk-COOR wherein R'" and Alk are as defined in thefirst instance. Examples of such compounds are listed in Tables I andII. In each of these instances intermedi- 15 ate of formula [II andketoester listed therein are used in an equivalent amount to theintermediate of formula Ill and ketoesters listed in Examples 3 and 4(Procedure A). Note that in each of these instances an ester -isobtained prior to hydrolysis. This ester is the corre- 20 spondingintermediate of formula V in which 2 is COOR or AlkCO()R" wherein R islower alkyl and Alk' is defined in the first instance, the alkyl portionof said ester being derived from the R portion of the ketoester offormula [V employed therein.

Likewise, the procedure of Example 4 (Procedure 8) may be used toprepare the products listed in Tables I and 1] except that in this casean equivalent amount of the corresponding ketoacid of formula IV is usedinstead of the ketoester listed in the table.

TABLE 1 Intermediate of Ketoester of Formula lV, Product: (Prefix ListedExample Formula III in which x is OH l-(Suffix Listed Below) R R" R R R"R AIM-C0 R'" Prefix/[Suffix 5 H H H H H CH CH ('0 H LlU-dimethyl/lcarboxylic acid 6 CH; H H H H CH (,H,, CO C H, l-ethyl-3.l0-dimethyl//carhoxylic acid 7 n-C H H 5-CH, CH n-C;,H CO CH l,3-diisopropyl-8 l0-dimethylllcarboxylic acid 8 CH CH. H H S-OH CH CH (O CH; X-hydroxy-IJJJOtetramethyl/l carhoxylic acid 9 H H 7-c,H H n-C -,H, CO CHfiJU-diethyl-l-propyl/l carboxylic acid l0 H H i-C H; H H i(' -,H; D COCH l-cyclopropyl-4 l0- diisopropyll/ carhoxylic acid 1 l cu, CH, H, H, HC H 0 co CH l-cyclopentyl 4,4,l0-

triethyl-3,3dimcthyl// carboxylic acid 13 H H CH H H CH CH CH,CO H L4,lU-trimethyl/l acetic acid n H H H H CH, C .H,, CH CO C. .H,,LethyI-lU-mcthyl/l acetic acid l4 H H H H CH n-C H CH CO C Hl0-mcthyl-l-propyl// acetic acid, m.p.

I46I4XC. 15 H H H H H CH i-C;,H (H CO C. ,H l-isopropyl-lll-mcthyl/lacetic acid In CH H H H CH n-C H CH CO C .H 3.10-dimcthyll-prupylllacetic acid l7 CH; H (1H CH H CH; H CH CO H l.4-diethyl-3,l0-

dimcthyll/acetic acid l8 H H H H H CH;, CH C'HtCH-JCO H a,ll()-triniethyl// acetic acid l) H H H H H (:H; O C(CHJJCO C .Hl-cyclohexyl-ill-ethyl.

mar-dimcthyll/acetic acid 20 H H H H H CH t-C,H,, CH CO H,l-t-bulyll0-methyll/ acetic acid Example Intermediate 0f Formula ill inwhich x is OH TABLE I Continued Ketoester of Formula IV7.y-dicthyll-prupyl 3.3. l()-trimcth vl// butyric acid l-hutyl-J.lU-dicthyl7- nitr0-or.l3,7-trin1clhyll/ butyric acidafi-diethyl-3,3-dimethyll ,9, l U-triprupyl/l hutyric acidhydroxy-a,a.7;ytetramethylllbutyric acid l0-t-butyl-9-ethoxy- I y mmfi,0x734- octomethyl /butyric acid TABLE ll Example Intermediate of FormulaIII in which X is SH RFI Ketoester of Formula IV,

CH" co CH,

to CH3 CHBCO (3H CH. ,CO c n,

C(CHmCO C.,H,

Product: (Prefix Listed Bcl0w)-3,4- Dihydrol H- 1 4-Thiazmc-[4.3-alindolel (Suffix Listed Below) LIU-dimcthyll/ carhoxylic acidl-cthyl3,lUdimcthyl// carhoxylic acid 1.3-diisopropyl-8. l U-methyll/carlmxylic acid S-hydmxyl 3,3 l (L tclramethyll/ carbuxylic acid6, l 0-dicthyll -prupyll/ carhuxylic acid l-cycl0pmpyl-4 ll)-diisopropyll/ carboxylic acid TABLE II Continued Intermediate ofKetoester of Product: (Prefix Formula IV, Listed Below)-3,4-

O Dihydrol H- l ,4-Thiazineoxazino[4,3-a]indole-l-acetamide (V; R and RCH R R, R", R and R H, X O and Z CH CONHC H Triethylemine (6 g.) andthen ethyl chloroformate (5 g.) are added to a cooled solution (5C.) ofl,l0- dimethyl-3,4-dihydro-1H- l,4-oxazino[4,3-a]indole-lacetic acid l0g.), described in Example 3, in [50 ml. of tetrahydrofuran (THF). Afterbeing stirred for 2 hr. at [0C. the suspension is further cooled to ca.lOC. and treated with methylamine (66 ml. ofthe 40% water solution) andstirred at given temperature for an additional hour. Most of the THF isevaporated and the residue partitioned between ether and water. Theether solution is washed with water, dried (MgSO and concentrated toafford a solid. The solid is recrystallized from ethyl acetate to affordthe title compound, m.p. l3l l33C.

In the same manner but replacing the 40% aqueous solution of methylaminewith an equivalent amount of the amines of formula HNRR, ammoniumhydroxide (concentrated), dimethylamine aqueous solution), n-hexylamine(20% aqueous solution), diethylamine (30% aqueous solution),isopropylamine aqueous solution), ethylamine (70% aqueous solution),pyrrolidine (50% aqueous solution), piperidine, morpholine,N-methylpiperazine,

l, l (J-dimethyl-3,4-dihydro l H-] ,4-oxazino[4,3-a]indole-l-acetamide,m.p. l56 l57C., nmr (CDCl 5|.69 (3H), 2.33 (3H),

N,N, l l O-tetramethyl-3,4-dihydrol H- l ,4-

l, l O-dimethyl-N-hexyl-3,4-dihydrol H-] ,4 oxazino[4,3-a]indolel-acetamide,

N,N-cliethyl-l l O-dimethyl-3,4-dihydrol H- l ,4-

oxazino[4,3-a]-indolel -acetamide l,l0-dimethyl-N-isopropyl-3,4-dihydrolH- l ,4- oxazino[4,3-a]indolel -acetamide,

l ,10-dimethyl-N-ethyl-3,4-dihydrol H-1 ,4-oxazino[4,3-a]indole-l-acetamide, m.p. 114 1 16C., l-[( l, l0-dimethyl-3,4-dihydrol H-l ,4-oxazino-[4,3- a]indoll -yl )-acetyl]-pyrrolidine,

l-[( l, l 0-dimethyl-3,4-dihydro- 1 H- 1 ,4-oxazino[4,3-

a indol- 1 -yl)-acetyl ]piperidine,

4-[( l, l O-dimethyl-3,4-dihydrol H-l ,4-oxazino[4,3- alindol-1-yl)-acetyl]morpholine, and

1-methyl-4-[( 1,lO-dimethyl-3,4-dihydro-lH-l,4-oxazino[4,3-a]indol-1-yl)acetyl]piperazine, are obtained respectively.

By following the procedure of Example I07 but using as starting materialan equivalent amount of one of the acid compounds of formula V,described in Examples l4 to 106, instead of 3,4-dihydro-1,lO-dimethyl-3,4- dihydro- 1 H- l ,4-oxazino[4,3-a]indolel-acetic acid,and using an equivalent amount of an appropriate amine such as ammoniaor a primary or secondary amine described in Example lO7, then thecorresponding amide compound of formula V is obtained. Examples of suchamides are listed as products in Tables III, IV, V and VI together withthe appropriate starting material and amine used for the preparation ofthe amide. in each case the starting material is noted by the example inwhich it is prepared.

TABLE III NO. OF THE EXAMPLE IN WHICH STARTING MATERIAL ISlNDOLE-l-(SUFFIX LISTED BELOW)] EXAMPLE PREPARED AMINE PREFIX/ISUFFIXl0?) 4 H NH NJ. l(I-trimcthyll/pnipionarnide m.p. l47- [49C. l ()9 4 NH;l, l ll-dimethylHpropionamide,

m. v )7 97C. l l() 4 (CH:,). .NH N,N l ,lU-tclrameth lflpropionamidc,nmr ICDCLIl 51.64 (3H). 133(3H), 2.83 ((iH) I l I 4 C H NHl,l(I-dimethyl-Nethyll/ prupionamide, mp. 104 106C 1 l 4 IC HQ NHN,N-dicthyll l U-dimuthyljl propionuniitlc 1 l3 5 C'H; NH- N, l|ll-trimethyl/lcarlxmumitlu l4 5 NH;, 1, l U-dimethyl/[carhoxamidc l5 6(CH;,) NH l-ethyl-N,N,3 l (Ltctrantcthylflf carhoxamidc 1 lo 7n-(',,H,;;NH i B-KiliSUPFUPyi-X,iU-kiil1iClh)l-N TABLE III Continued NO,OF THE EXAMPLE IN WHICH STARTING PRODUCT: PREFIX LISTED BELOW)- TABLE VNO OF THE EXAMPLE IN WHICH STARTING Continued PRODUCT: [PREFIX LISTEDBELOW)- 3 4-DIHYDRO- I H- I .4THIASINO[ 4,3-3 I-N,N-diethy1-l,l0-dimethyl-3,4-dihydro-1H-l,4- oxazino 4,3-a 1 indolel-acetamide, 1.10-dimethyl-N-isopropyl-3,4-dihydro1H-1,4-oxazino[4,3-a]indolel-acetamidc 1 ,10-dimethyl-N-ethyl-3,4-dihydro- 1 H-l ,4-

oxazino[ 4,3-a ]indlcl -acctamide 1-[( 1 ,10-dimethy1-3,4-dihydro-1H-1,4-oxazino[4,3- a]indol-1-y1)acety1]pyrro1idine,

l[( l, l 0-dimethyl-3,4-dihydro- 1 H- 1 ,4-oxazino[4,3- a]indo1- 1 -y1)acety1]piperidinc,

4-[( 1,10-dimethy1-3,4-dihydro-l-l,4-oxazin0[4,3-a]indol-1y1)acety1]morpho1ine, and

1 -methyI-4-[ 1, 1 0-dimethy1-3,4-dihydro- 1 H- 1 ,4-oxazino[4,3-a]indol-1-y1)acctyl]piperazine, then there are obtained,

1-(2-aminoethyl)-l ,10-dimethy1-3,4-dihydro-1H,l ,4-oxazino[4,3-a]ind0lc, nmr (CDCI;,) 81.62 (3H), 2.34

1 ,IO-dimethyl-1-[(2-dimethylamin0)ethyl]-3,4- dihydrol H- l,4-oxazinol4,3-a]indole, nmr (CDCl 81.60 (3H), 2.30 (3H),

corresponding hydrochloric acid addition salt (hydrochloride) has m.p.237 239C, after recrystallization from methanol-ether,

1,10-dimethy1- 1 -[2-( hexylamino )ethyl ]-3,4-dihydro- 1 H- 1,4-oxazino[4,3-a]indole,

1-[ 2-( diethylamino )ethyl 1 1 O-dimethyl-3,4-dihydrolH-l,4-oxazino[4,3-a]indole, nmr (CDCl 81.60 (3H), 2.30 (3H),corresponding hydrobromic acid addition salt (hydrobromide) has m.p. 191193C, after recrystallization from isopropanol-ether, 1,10- dimethyll2-( isopropylamino)ethyl ]-3,4-dihydr0- l H- 1 ,4-oxazino[ 4,3-a1indo1e.l,10-dimethyl-l-[2-(ethylamino)ethyl]-3,4-dihydro-1H-l,4-oxazino[4,3-a]indole, nmr (CDCl 81.58

(3H), 2.32 (3H), corresponding hydrobromic acid addition salt has m.p.196 198C, after recrystallization from isopropanol-ether,

l,10-dimethy1-l-[2-( l-pyrrolidinyl )ethyl]-3,4-dihydrolH-l,4-oxazino[4,3-a]indo1e, nmr (CDC1 81.60 (3H), 2.30 (3H), corresondinghydrochloric acid addition salt has m.p. 223 225C, afterrecrystallization from isopropanol-ether,1,10-dimethyl-1-(2-piperidinoethyl)-3,4-dihydro-1H-l,4-oxazino[4,3-a]indo1e, nmr (CDCl 81.61 (3H), 2.33 (3H), correspondinghydrobromic acid addition salt has m.p. 253 255C, afterrecrystallization from methanol,

1 ,10-dimethyl-l-(2-morpholinoethyl)-3,4-dihydro-1H-l,4-oxazino[4,3-]ind0le, nmr (CDCl 51.60 (3H), 2.31 (3H), correspondinghydrochloric acid addition salt has m.p. 234 236C, afterrecrystallization from isopropanol-ether, and

1 ,10-dimethyl-1-[2-(4-methyl-l piperazinyl)ethy1]- 3 ,4-dihydrol H- 1,4-oxazino[4,3a]indo1e, nmr (CDCl 81.62 (s, 3H), 2.32 (s, 3H)corresponding maleic acid addition salt (dimaleate) has m.p. 196 198C,after recrystallization from methanol, respectively.

By following the procedure of Example 284 but using as starting materialan equivalent amount of one of the amide compounds of formula V,described in Examples 108 to 283 instead of NJ,10-trimethyl-3,4-dihydro-1 H- 1 ,4-oxazino[4,3-a]indolel -acetamide, then the correspondingcompounds of formula I are obtained. Examples of such compounds offormula 1 are listed as products in Tables V11 and V111 together withthe appropriate starting material. In each case the starting material isnoted by the example in which it is prepared.

TABLE V11 STARTING MATERIAL IS EXAMPLE NO OF EXAMPLE IN WHICH PREPAREDINDOLE 108 1, 1 O-dimethyl- 1 3-( methylamino propyl]. nmr (CDCI,,)8L62(3H). 2.32 (3H), corresponding hydrochloric acid addition salt has m.p.193 195C, after recrystallization from isopropanol ether 1 Laminopropyl1 IO-dimethyl, nmr(CDC1 )51.58 (3H), 1.90 (2H), correspondinghydrochloric acid addition salt has mp 204 206C, after recrystallizationfrom methanol-ether 1 HLdimcthyl- 1 3-(dimethy1amino)- propyl], nmr(CDC1,)6I.64 (3H), 2.33 (3H), 2.35 (4H). corresponding hydrochloric acidaddition salt has m.p. 200 201C, after recrystallization frommethanol-ether 1 1 U-dimcthyll 3-( cthylamino propyll, nmr (CDCI,) 81.61(3H). 2,33 (3H). corresponding, hydrochloric acid addition salt has mp220 222C, after recrystallization from ethanol-ether1-[3-(dicthylaminoH-l.10-

dimcthyl. nmr (CDCI,,) 8094 (t, 6H),

1.58 (s. 3H). corresponding hydrohromic acid addition salt has m.p, 174176C., after recrystallization from isopropanol l, 1 O-dimcthyl- 1methylamino )mcthyl) l-(aminomethyl 1,1(l-dimcthy1 1|(dimcthylaminmmcthyl 1 -ethy1- 1,3, 1 U-trimcthyl l.3-diisopropyl8,ltbdimethyb 1 [hcxylamino )mcthyl 1-( ethylamino )mcthyLKhydroxy- 1,3.3.l1ltctrameth \'1

1. A PROCESS FOR PREPARING A COMPOUND OF FORMULA 1
 2. The process ofclaim 1 in which the compound of formula I is reacted with apharmaceutically acceptable acid to give the corresponding acid additionsalt.
 3. The process of claim 1 in which R1 is methyl, R2, R3, R4, R5and R6 are hydrogen, R7 is methyl, X is oxy, R8 is hydrogen, R9 ismethyl, Alk3 is CH2CH2, X1 is hydroxy and Z is CH2COOC2H5.
 4. Theprocess of claim 1 in which R1 is methyl, R2, R3, R4, R5 and R6 arehydrogen, R7 is methyl, X is oxy, R8 is hydrogen, R9 is hydrogen, Alk3is CH2CH2, X1 is hydroxy and Z is CH2COOC2H5.
 5. The process of claim 1in which R1 is methyl, R2, R3, R4, R5 and R6 are hydrogen, R7 is methyl,X is oxy, R8 is methyl, R9 is methyl, Alk3 is CH2CH2, X1 is hydroxy andZ is CH2COOC2H5.
 6. The process of claim 1 in which R1 is methyl, R2,R3, R4, R5 and R6 are hydrogen, R7 is methyl, X is oxy, R8 is ethyl, R9is ethyl, Alk3 is CH2CH2, X1 is hydroxy and Z is CH2COOC2H5.
 7. Theprocess of claim 1 in which R1 is methyl, R2, R3, R4, R5 and R6 arehydrogen, R7 is methyl, X is oxy, R8 is hydrogen, R9 is ethyl, Alk3 isCH2CH2, X1 is hydroxy and Z is CH2COOC2H5.
 8. The process of claim 1 inwhich R1 is methyl, R2R3, R4, R5 and R6 are hydrogen, R7 is methyl, X isoxy, R8 and R9 together with the nitrogen atom to which they are joinedform a 1-pyrrolidinyl, Alk3 is CH2CH2, X1 is hydroxy and Z isCH2COOC2H5.
 9. The process of claim 1 in which R1 is methyl, R2, R3, R4,R5 and R6 are hydrogen, R7 is methyl, X is oxy, R8 and R9 together withthe nitrogen atom to which they are joined form a piperidino, Alk3 isCH2CH2, X1 is hydroxy and Z is CH2COOC2H5.
 10. The process of claim 1 inwhich R1 is methyl, R2, R3, R4, R5 and R6 are hydrogen, R7 is methyl, Xis oxy, R8 and R9 together with the nitrogen atom to which they arejoined form a morpholino, Alk3 is CH2CH2, X1 is hydroxy and Z isCH2COOC2H5.
 11. The process of claim 1 in which R1 is methyl, R2, R3,R4, R5 and R6 are hydrogen, R7 is methyl, X is oxy, R8 and R9 togetherwith the nitrogen atom to which they are joined form a4-(methyl)-1-piperazinyl, Alk3 is CH2CH2, X1 is hydroxy and Z isCH2COOC2H5.
 12. The process of claim 1 in which R1 is methyl, R2, R3,R4, R5 and R6 are hydrogen, R7 is methyl, X is oxy, R8 is hydrogen, R9is methyl, Alk3 is CH2CH2CH2, X1 is hydroxy and Z is CH2CH2COOC2H5. 13.The process of claim 1 in which R1 is methyl, R2, R3, R4, R5 and R6 arehydrogen, R7 is methyl, X is oxy, R8 is hydrogen, R9 is hydrogen, Alk3is CH2CH2CH2, X1 is hydroxy and Z is CH2CH2COOC2H5.
 14. The process ofclaim 1 in which R1 is methyl, R2, R3, R4, R5 and R6 are hydrogen, R7 ismethyl, X is oxy, R8 is methyl, R9 is methyl, Alk3 is CH2CH2CH2, X1 ishydroxy and Z is CH2CH2COOC2H5.
 15. The process of claim 1 in which R1is methyl, R2, R3, R4, R5 and R6 are hydrogen, R7 is methyl, X is oxy,R8 is hydrogen, R9 is ethyl, Alk3 is CH2CH2CH2, X1 is hydroxy and Z isCH2CH2COOC2H5.
 16. The process of claim 1 in which R1 is methyl, R2, R3,R4, R5 and R6 are hydrogen, R7 is methyl, X is oxy, R8 is ethyl, R9 isethyl, Alk3 is CH2CH2CH2, X1 is hydroxy and Z is CH2CH2COOC2H5.
 17. Theprocess of claim 1 in which R1 is propyl, R2, R3, R4, R5 and R6 arehydrogen, R7 is methyl, X is oxy, R8 is methyl, R9 is methyl, Alk3 isCH2CH2, X1 is hydroxy and Z is CH2COOC2H5.
 18. The process of claim 1 inwhich R1 is propyl, R2, R3, R4, R5 and R6 are hydrogen, R7 is methyl, Xis oxy, R8 is ethyl, R9 is ethyl, Alk3 is CH2CH2, X1 is hydroxy and Z isCH2COOC2H5.
 19. The process of claim 1 in which R1 is methyl, R2, R3,R4, R5 and R6 are hydrogen, R7 is methyl, X is oxy, R8 and R9 togetherwith the nitrogen atom to which they are joined form a 1-pyrrolidinyl,Alk3 is CH2CH2CH2, X1 is hydroxy and Z is CH2CH2COOC2H5.
 20. The processof claim 1 in which R1 is methyl, R2, R3, R4, R5 and R6 are hydrogen, R7is methyl, X is oxy, R8 and R9 together with the nitrogen atom to whichthey are joined form a piperidino, Alk3 is CH2CH2CH2, X1 is hydroxy andZ is CH2CH2COOC2H5.
 21. The process of claim 1 in which R1 is methyl,R2, R3R4, R5 and R6 are hydrogen, R7 is methyl, X is oxy, R8 and R9together with the nitrogen atom to which they are joined form amorpholino, Alk3 is CH2CH2CH2, X1 is hydroxy and Z is CH2CH2COOC2H5. 22.The process of claim 1 in which R1 is methyl, R2, R3, R4R5 and R6 arehydrogen, R7 is methyl, X is oxy, R8 and R9 together with the nitrogenatom to which they are joined form a 4-(methyl)-1-piperazinyl, Alk3 isCH2CH2CH2, X1 is hydroxy and Z is CH2CH2COOC2H5.